Intracranial ependymomas in children: society of pediatric oncology experience with postoperative hyperfractionated local radiotherapy.

PURPOSE: To prospectively investigate the role of local hyperfractionated radiotherapy (RT) after surgical resection in the treatment of intracranial ependymomas in children. PATIENTS AND METHODS: Postoperative local hyperfractionated RT was proposed for every child (>5 years old at diagnosis) with localized intracranial ependymoma. The planned dose was 60 Gy after complete resection (CR) and 66 Gy after partial resection, delivered in two daily fractions of 1 Gy, according to the early postoperative imaging findings. RESULTS: Between November 1996 and December 2002, 24 children with infratentorial (n = 20) or supratentorial (n = 4) intracranial ependymoma were included. The median age was 8.6 years (range, 5-17). The World Health Organization grade was anaplastic in 10 of the 24 patients (not assessable in 1). After a retrospective central review, a CR was reported in 16 patients, partial resection in 4, and doubtful resection in 4. The radiation dose was 60 Gy in 18 cases (one partial resection), 66 Gy in 5 cases (one CR), and 54 Gy in 1 case (CR). The 5-year overall survival rate was 74.8%, and the progression-free survival rate was 54.2%. Of the 24 patients, 11 developed a relapse: 7 local only and 4 metastatic and local. The histological grade and extent of resection were not prognostic factors. More than 3 in 4 children had no sequelae of RT at a median follow-up of 7 years (95% confidence interval, 66.4-90.0 months). CONCLUSION: The results of our study have shown that hyperfractionated RT is safe but provides no outcome benefit compared with other strategies of RT such as standard fractionated regimens.

Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics.

Medulloblastoma is the most frequent malignant paediatric brain tumour. The activation of the Wnt/beta-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favourable patient outcome. We report a series of 72 paediatric medulloblastomas evaluated for beta-catenin protein expression, CTNNB1 mutations, and comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of beta-catenin showed extensive nuclear staining (>50% of the tumour cells) in six cases and focal nuclear staining (<10% of cells) in three cases. The other cases either exhibited a signal strictly limited to the cytoplasm (58 cases) or were negative (five cases). CTNNB1 mutations were detected in all beta-catenin extensively nucleopositive cases. The expression profiles of these cases documented strong activation of the Wnt/beta-catenin pathway. Remarkably, five out of these six tumours showed a complete loss of chromosome 6. In contrast, cases with focal nuclear beta-catenin staining, as well as tumours with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/beta-catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow-up of 75.7 months (range 27.5-121.2 months) from diagnosis. All three patients with focal nuclear staining of beta-catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1-mutated tumours represent a distinct molecular subgroup of medulloblastomas with favourable outcome, indicating that therapy de-escalation should be considered. International consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved.

Pediatric infratentorial gangliogliomas: a retrospective series.

OBJECT: The aim of this study was to retrospectively review the clinical presentation, the roles of surgery and adjuvant therapy, and the treatment-related morbidity in children with a ganglioglioma in the posterior fossa and to try and determine the prognostic factors. METHODS: Between 1991 and 2006, 10 children were treated for a posterior fossa ganglioglioma at the authors' institution. The mean age of the children, the duration of symptoms prior to diagnosis, and the follow-up were 8.2, 2.4, and 3.9 years, respectively. Nine of the children presented with symptoms of raised intracranial pressure. Preoperative imaging showed enhancement in all patients; in eight it was in a patchy distribution. The operations consisted of radical resection (> 75%) in seven children, biopsy in two, and a total macroscopic excision in one. RESULTS: The surgical procedure did not cause deterioration in the neurological condition in any of the children. There was no recurrence in the child who underwent total macroscopic excision of the tumor, and there has been no tumor progression in three children, two of whom have had no evidence of enhancement of the postoperative residual tumor. The tumor has progressed in six children, requiring further surgery in three, chemotherapy in four, and radiotherapy and second-line chemotherapy in one child to control the tumor. CONCLUSIONS: The imaging of gangliogliomas in the posterior fossa showed patchy enhancement. The patients in whom it was possible to achieve a radical resection, aimed at removing at least the enhancing portion of the tumor, have not required further treatment. A second excision, for progressive tumors, is an effective adjuvant therapy.

Pleomorphic xanthoastrocytoma of the cerebellopontine angle in a child.

CASE REPORT: The case of a 6-year-old girl with a pleomorphic xanthoastrocytoma (PXA) in the left cerebellopontine angle (CPA) is reported. The clinical, radiological, and histopathological findings are presented. DISCUSSION: To our knowledge, the presence of PXA in the CPA has not previously been reported. The rare infratentorial locations of PXA (frequently seen in association with ganglioglioma) are reviewed, as well as the other infrequent locations of this tumor. This report adds to the list of differential diagnoses of CPA tumors in children.

p53 Pathway dysfunction in primary childhood ependymomas.

BACKGROUND: Childhood ependymoma remains a major therapeutic challenge despite surgery, chemotherapy, and irradiation. We hypothesized that p53 function might be abrogated in ependymomas and implicated in their resistance to anti-cancer therapy. PROCEDURE: Primary ependymomas at diagnosis or relapse from 24 children were analyzed for p53 pathway, using a functional assay in yeast, RT-PCR, Western blot analysis, and/or immunohistochemistry for TP53 mutation, p14(ARF) deletion and promoter hypermethylation, MDM2 and PAX5 expression, respectively. p53-mediated response to radiation-induced DNA damage was evaluated using Western blot and flow cytometry analysis in two ependymoma xenograft models, IGREP37 and IGREP83, derived from primary anaplastic childhood ependymomas. RESULTS: No TP53, MDM2, p14(ARF), PAX5 gene abnormalities were detected in the primary ependymomas tumors and xenografts tested. Interestingly, despite the lack of these abnormalities, p53 induced p21-mediated G(1) growth arrest in response to irradiation was altered in the IGREP37 xenograft tumors. Although irradiation induced necrosis and apoptotic cell death, IGREP37 tumors were moderately sensitive to radiation therapy in vivo. In contrast, irradiation yielded significant tumor growth delays and tumor regressions in the p53 functional IGREP83 xenografts. CONCLUSION: Alterations in p53-mediated growth arrest in ependymomas might be implicated in the radio-resistance of these tumors and demand further evaluation.

Surgical implications of the thickened pituitary stalk accompanied by central diabetes insipidus.

OBJECT: The authors discuss the indications for and timing of a diagnostic neurosurgical procedure in children with diabetes insipidus (DI) and a thickened pituitary stalk (TPS) on magnetic resonance (MR) imaging. METHODS: Seven children with a TPS who presented with DI eventually underwent surgery for diagnostic purposes. The ages at onset of DI were 6 to 16 years, and the follow-up period until surgery was 26.9 +/- 11.9 months. In four of seven children, the stalk appeared normal on the first MR image, but it was thickened and variably enhancing on later images in all instances. The reason for eventual surgery was endocrinological deterioration in two of seven children, radiological progression in two children, and a combination of the two in three children. Three children experienced visual disturbances and four children had optic nerve, chiasma, or hypothalamus involvement. All children suffered additional endocrinological abnormalities pursuant to the initial DI. A definitive diagnosis was achieved in six of seven children: germinomas in five and Langerhans cell histiocytosis in one. One child had lymphocytic infiltrate. None of the children deteriorated neurologically or endocrinologically after the operation. On follow up, vision deficit was irreversible in all children who demonstrated visual abnormalities before treatment. CONCLUSIONS: Surgery should be performed in children with a TPS and DI for early diagnosis and disease-oriented therapy when there is further endocrinological, radiological, or clinical deterioration. The complication rate is low in open biopsies, and histological diagnosis is achieved in most of the cases. All children who present with central DI must undergo head MR imaging, and even if results are normal, close radiological and clinical follow up is mandatory.

Preoperative chemotherapy in children with high-risk medulloblastomas: a feasibility study.

OBJECT: The authors set out to evaluate the feasibility and effectiveness of preoperative chemotherapy in treating high-risk medulloblastomas. METHODS: Between 1997 and 2000, 21 children with high-risk medulloblastomas (M > or = 2 and/or T3b/T4 according to the Chang classification) were treated consecutively in a pilot study. The protocol began with treatment of the hydrocephalus and confirmation of the diagnosis. Tumor surgery was performed either after conventional chemotherapy (eight patients) or after subsequent high-dose chemotherapy (HDCT; 11 patients). Two children with early leptomeningeal progression died before surgery. Craniospinal irradiation was applied to children older than 5 years of age, whereas younger children received local irradiation only. Hydrocephalus was present in 17 children and was treated with ventriculocisternostomy in 13 and shunt insertion in four. A biopsy procedure was performed with a stereotactic frame in 10 children, an open surgery was performed in four, an endoscope was used during the ventriculocisternostomy in three, and the diagnosis was made based on cerebrospinal fluid cytological analysis in two. The response rate to the first two courses of chemotherapy was 71% for the tumor and 59% for the metastases. The pathological analysis of the residue after chemotherapy showed true medulloblastomas in seven cases, complete neuroglial maturation in three cases, and a mixture of both in nine cases. Three-year progression-free survival was 37% and was significantly better in children older than 5 years of age. There was one death related to the HDCT. CONCLUSIONS: Preoperative chemotherapy is feasible and safe in children with high-risk medulloblastomas provided that the hydrocephalus can be treated at diagnosis. A larger study is warranted to ensure that the high response rate to adjuvant chemotherapy can lead to better surgical results and survival advantage.

Antiglial cell autoantibodies and childhood epilepsy: a case report.

We report the case of a patient with severe partial epilepsy associated with a focal rolandic, pathologically proven, cortical dysplasia. By measuring intracellular calcium concentrations, functional antiglial non-glutamate receptor 3 (GluR3) autoantibodies were identified in the serum of this patient. Antineuronal autoantibodies, which interfere with GluR3-receptor function, also were detected. This observation provides new clues about the involvement of immunologic mechanisms in epileptic disorders.

Fourth ventricle neurocytoma with lipomatous and ependymal differentiation.

We report the case of a 4-year-old girl with a fourth ventricle tumor diagnosed as a cerebellar liponeurocytoma which recurred, showing ependymal differentiation, 14 months after surgery. Magnetic resonance imaging at initial presentation revealed a large mass in the fourth ventricle, and histology showed a neoplasm characterized by a combination of well-differentiated neurocytes and cells resembling adipocytes. The tumor recurrence was histologically identical to the original tumor in some regions, but with fewer adipose-like cells, while other areas presented an endocrine architecture with oligo-like or pleiomorphic cells, and rosette-like arrangements of tumoral cells were seen around the thin vessels, with features similar to cellular ependymoma. The cells in the liponeurocytoma areas expressed synaptophysin, chromogranin A, and epithelial membrane antigen. Glial fibrillary acidic protein was expressed in some dispersed tumoral cells, in lipidized tumoral cells, and in reactive astrocytes. Cytokeratin was focally expressed in the ependymal region of the recurrence. The immunophenotype of our case, with glial, ependymal, and neuronal or neuroendocrine markers, suggest a neurocytoma with lipomatous and ependymal differentiation. This tumor resembled those derived from circumventricular organs. Its localization in the area postrema region led us to hypothesize that it may be derived from this circumventricular organ.

Angiocentric neuroepithelial tumor (ANET): a new epilepsy-related clinicopathological entity with distinctive MRI.

Several types of glioneuronal tumors are known to induce intractable partial seizures in children and adults. The most frequent are dysembryoplastic neuroepithelial tumors (DNETs) and gangliogliomas. We report here a new clinicopathological entity within the spectrum of glioneuronal tumors observed in 10 children who underwent surgery for refractory epilepsy. These tumors demonstrate a unique, pathognomonic histological pattern and a specific appearance at magnetic resonance imaging (MRI). The most striking neuropathological feature is an angiocentric polarity of the tumor with gliofibrillary acidic protein (GFAP) positive fusiform and bipolar astrocytic cells arranged around blood vessels (perivascular cuffing with tumoral astrocytes). Characteristic MRI findings include involvement of cortical gray and white matter, intrinsically high signal on T1-weighted images, as well as a stalk like extension to the ventricle. Immunohistochemical neuronal markers (neurofilament protein, synaptophysin and chromogranin) confirm the presence of a neuronal cell component. Therefore, the term angiocentric neuroepithelial tumor (ANET) is proposed.

Unusual presentation of GM2 gangliosidosis mimicking a brain stem tumor in a 3-year-old girl.

We report a case of GM2 gangliosidosis revealed by MR imaging of an isolated brain stem abnormality in a 3-year-old girl referred for gait difficulties related to ataxia and pyramidal signs. Brain MR imaging displayed a brain stem lesion with high signal intensity on fluid-attenuated inversion recovery and T2-weighted images, suggesting either a tumor or an inflammatory process. Stereotactic biopsy findings showed the presence of swollen neurons with storage material in lysosomes. Enzyme study revealed deficiency of hexosaminidase A, variant B1. Gangliosidoses should be considered in the differential diagnosis of isolated infiltrating brain stem lesions in childhood.

Comparative genomic hybridization detects specific cytogenetic abnormalities in pediatric ependymomas and choroid plexus papillomas.

Pathogenesis and genetic abnormalities of ependymomas are not well known and differential diagnosis with choroid plexus tumors may be difficult when these tumors are located in the ventricles. We analyzed 16 samples of primary pediatric ependymomas and seven choroid plexus tumors for significant gains or losses of genomic DNA, using comparative genomic hybridization (CGH). Four ependymoma samples were obtained after surgery for relapse, including one patient whose tumor was analyzed at diagnosis and at first and second relapses. Three out of 16 ependymomas and none of the choroid plexus tumors appeared normal by CGH. In the remaining ependymomas, the number of regions with genomic imbalance was limited. The most frequent copy number abnormality in ependymomas was 22q loss. In one patient from whom multiple samples could be analyzed during tumor progression, no abnormality was present at diagnosis; gain of chromosome 9 and loss of 6q were observed at first relapse and, at second relapse, additional genomic imbalances were loss of 3p, 10q, and chromosome 15. In choroid plexus tumors, recurrent abnormalities were gains of chromosome 7 and region 12q. The recurrent chromosomal abnormalities were clearly different between ependymomas and choroid plexus papillomas (CPP). Recurrent loss of 22q suggests that this region harbors tumor suppressor genes important in the pathogenesis of ependymomas; however, other pathogenic pathways may exist involving 6q and chromosome 10 losses or gain of 1q and chromosome 9. CPP can be distinguished from ependymoma on the basis of CGH abnormalities.